key: cord-0995814-te2jz2gn authors: Leino, Annamari; Lukkarinen, Minna; Turunen, Riitta; Vuorinen, Tytti; Söderlund-Venermo, Maria; Vahlberg, Tero; Camargo, Carlos A.; Bochkov, Yury A.; Gern, James E.; Jartti, Tuomas title: Pulmonary function and bronchial reactivity 4 years after the first virus-induced wheezing date: 2018-10-08 journal: Allergy DOI: 10.1111/all.13593 sha: 3a24f34693d064d96d48ce3c7a69b2d125127394 doc_id: 995814 cord_uid: te2jz2gn BACKGROUND: Wheezing illnesses among young children are common, and are a risk factor for asthma. However, determinants of childhood bronchial reactivity, a key feature of asthma, are largely unknown. Aim of this study was to determine how patient characteristics during the first severe virus-induced wheezing episode are associated with pulmonary function at pre-school age. METHODS: Study consisted of 76 children presenting with their first wheezing episode at the ages of 3 to 23 months. At study entry, viral etiology, rhinovirus genome load, atopic and clinical characteristics, and standardized questionnaire were analyzed. At 4-year follow-up visit, impulse oscillometry with exercise challenge was performed. RESULTS: At study entry, the mean age of the children was 12 months (SD 6.0), 57 (75%) were rhinovirus positive and 22 (30%) were sensitized. At follow-up visit four years later, the mean age of the children was 60 months (SD 7.9) and 37 (49%) were using asthma medication regularly (discontinued before testing in 25 [68%] children). Bronchial reactivity (≥35% change in mean crude values of resistance) after exercise challenge or bronchodilation was present in 9 (12%) children. Children with atopic sensitization at the time of the first wheezing episode were more often likely to develop bronchial reactivity (odds ratio 8.8, P = .03) than the children without sensitization. No other significant associations were found. CONCLUSIONS: Atopic sensitization at the time of the first severe wheezing episode is an important early risk factor for increased bronchial reactivity at pre-school age. than the children without sensitization. No other significant associations were found. Conclusions: Atopic sensitization at the time of the first severe wheezing episode is an important early risk factor for increased bronchial reactivity at preschool age. bronchial reactivity, impulse oscillometry, pulmonary function, sensitization, wheezing Previous studies have shown that early wheezing induced by rhinovirus and/or associated with sensitization is an important risk factor for recurrent wheezing and asthma. They are likely to reveal the underlying airway inflammation and the weaknesses in viral defense mechanisms. [1] [2] [3] However, the factors influencing bronchial reactivity in children are poorly characterized. Previous studies have shown that early-life factors, such as early-onset atopy, 4-7 family history of asthma, 6, 8 maternal smoking, [4] [5] [6] 8, 9 exposure to traffic-related air pollution, 10, 11 preterm birth, [12] [13] [14] and low birth weight, 15 may be associated with decreased pulmonary function in later childhood. Two studies have shown that wheezing at young age, induced by rhinovirus, may be associated with decreased pulmonary function or increased airway reactivity later in childhood. 8, 16 Some 5,17,18 but not all 9, 19 studies have shown a comparable association between respiratory syncytial virus (RSV)-induced wheezing and reduced pulmonary function. However, these earlier studies mainly included older children, and there were no data from the first virus-induced wheezing episode. Pulmonary function testing in young children is challenging. Impulse oscillometry (IOS) is a method for testing pulmonary function during tidal breathing. [20] [21] [22] [23] A key measurement in IOS is respiratory resistance (Rrs) which indicates the energy loss due to resistive forces to the airflow in the airways and is clinically interpreted as an indicator of obstruction. IOS is child-friendly as it requires a minimum cooperation and has successfully been used from the age of 2-3 years forward. 21, 24 In Finland, there are population-based reference values available for children aged 2-7 years. 20, 23 Secondary strategies to prevent asthma can be initiated at the time of the first wheezing episode. [25] [26] [27] [28] However, it is not known which patient characteristics at the time of the first acute wheezing episode predict abnormal pulmonary function during the later childhood. Thus, Vinku2 is the first study to investigate the associations between the patient characteristics of the first acute severe virus-induced wheezing episode and the subsequent pulmonary function and bronchial reactivity. Atopic sensitization diagnosed during the first acute severe wheezing episode was associated with increased bronchial reactivity and reduced lung function at preschool age. These results are important to consider for the design of early intervention trials for the secondary prevention of asthma. | 519 among children who had suffered from the first acute severe wheezing episode before the age of 2 years, we aimed to determine the pulmonary function at the age of 5 years and its reactivity to exercise or bronchodilation by IOS. We also tested for early-life factors predicting the exercise or bronchodilation-induced bronchial reactivity. We hypothesized that patient characteristics, such as rhinovirus etiology and atopy at the time of the first severe wheezing episode, would be associated with the pulmonary function and increased bronchial reactivity measured by IOS 4 years after the first wheezing episode. 2 | ME TH ODS This study is a part of a larger Vinku2 study which was carried out in the Turku University Hospital (recruitment June 2007 to March 2009). 3, 27, 29 The aim of the original study was to assess the effect of a 3-day course of oral prednisolone (first dose 2 mg/kg, then 2 mg/kg/ day in two divided doses, maximum dose 60 mg/day, Prednisolon ® 5 mg tablets, Leiras Takeda, Helsinki, Finland) in children with the first acute rhinovirus-induced wheezing episode (79% hospitalized; 21% treated at emergency room of tertiary hospital) using a randomized double-blind placebo-controlled paralleled design. The inclusion criteria were age 3-23 months, first acute wheezing episode (confirmed by parental report and medical records), and delivery at ≥36 weeks. Children with chronic nonatopic illnesses, need for intensive care unit treatment, or previous systemic or inhaled corticosteroid (ICS) treatment were excluded from the study. The study was approved by the Ethics Committee of the Turku University Hospital and was commenced after obtaining written informed consent from guardians. The trial was double-blinded until the 12-month follow-up. At study entry, the guardian completed a standard questionnaire form, the child was physically examined, a nasopharyngeal aspirate sample was taken using a standardized procedure, 30 At study entry, multiplex (Seeplex RV12 ACE Detection, Seegene, Seoul, Korea) or in-house single PCR tests were used for detecting adenovirus, coronavirus 229E, NL63 and HKU1, enteroviruses, human bocavirus, human metapneumovirus, influenza A and B viruses, parainfluenza virus types 1-3, rhinovirus types A, B, and C, and RSV A and B at the Department of Virology, University of Turku. 29 Rhinovirus sequencing has previously been described and analyzed in collaboration with the University of Wisconsin-Madison. 31, 32 Human bocavirus-1 was also analyzed using serology, as previously described. 33 To analyze the virus genome load, a sterile flocked swab (catalog number 502CS01, Copan, Brescia, Italy) was first dipped in the aspirate and then diluted with 1 mL of phosphate-buffered saline. The genome load was analyzed from RNA of rhinovirus-positive samples by a quantitative RT-PCR, using known concentrations of rhinovirus-B14 plasmid. The plasmid was received from Glyn Stanway at the University of Colchester (Essex, UK) and has been described elsewhere. 34 Serum levels of allergen-specific immunoglobulin E (IgE, Phadiatop Combi ® , Phadia, Uppsala, Sweden) and blood eosinophil counts (B- The airway hyperresponsiveness and reversible airflow obstruction were measured using IOS. [20] [21] [22] [23] The impulse oscillatory signals of 5-35 Hz were used and output pressure and flow signals analyzed for their amplitude and phase difference, to determine the airway resistance (Rrs, variable that reflects the energy loss due to resistive forces to the airflow) and the reactance (Xrs, indicator of viscoelastic properties of the small airways). Rrs and Xrs both are components of total respiratory impedance (Zrs, results from phase and pressure changes of the airflow). The frequency dependency of resistance (dRrs/df) was determined using linear regression through resistance data points Rrs5 and Rrs10. During obstruction, Rrs increases resulting in increased dRrs/df. Xrs decreases due to peripheral stiffening as a result of obstruction. The technical realization of IOS is described in more detail in Appendix S1. After the baseline measurements, a 6-minute exercise test was conducted. The children were urged to run 6-8 min at an exercise level where the heart rate was held at 85%-90% of their estimated maximum heart rate (205−1/2 × age), assessed with a heart rate monitor (Polar Sport Tester ® , Polar Elektro Ltd, Kempele, Finland). IOS measurement was repeated 1, 5, and 10 min after the exercise testing. 23, 35, 36 Finally, the reversible airflow obstruction was assessed with IOS 15 min after the bronchodilation with inhalation of 400 micrograms of salbutamol (Ventolin ® ) administered through a spacer (Babyhaler ® ); both products are from GlaxoSmithKline (Brentford, UK). 20 The results were proportioned by the height of the child. Rrs at 5 Hz was categorized as pathological if exercise-induced change in mean crude values was +35% or more 2 or if bronchodilator-induced change in mean crude values was −35% or more 23, 36 (Malmberg 2008 , Beydon 2007). Children had atopic sensitization if they had a positive test (cutoff level ≥0.35 kU/L) for IgE specific for any of tested allergens (codfish, cow's milk, egg, peanut, soybean, wheat, cat, dog, horse, birch, mugwort, timothy, Cladosporium herbarum, and Dermatophagoides pteronyssinus). 29 Eczema at study entry was a physician-made diagnosis according to pruritus, typical morphology, and chronicity of disease and it was defined as atopic if any sensitization was diagnosed. (95%) children. Exercise test was not conducted due to refusal of running in two (3%) children and due to severe asthma symptoms in one (1%) child. All the children with bronchodilation and/or exercise test (n = 76) were included in the analysis. The included (n = 76) and excluded (n = 48) participants did not differ from one another concerning the patient characteristics shown in Table 1 (Table S1 ). At study entry, the mean age of the 76 study subjects was 12 months (SD 6.0), 62 of them (82%) were hospitalized, and 50 In baseline IOS measurements, one (1%) child had a pathological Rrs Table 2 were not associated with the baseline values of IOS (Table S3 ). Baseline Rrs 10 values were not associated with any of the factors shown in Table 2 (data not shown). Increased bronchial reactivity was diagnosed in 9/75 (12%) children. Eight (11%) of these changes were diagnosed in the exercise test as a Rrs 5 Hz increase of ≥35%, and one (1%) of the children had a Rrs Likewise, other patient characteristics shown in Table 1 were not associated with bronchial reactivity. The OCS treatment during the first wheezing episode did not affect the pulmonary function four years later. There were no significant differences in baseline IOS parameters (all P ≥ 0.13) or in exerciseinduced bronchial reactivity (P ≥ 0.16) between the prednisolone and placebo groups. In the 12 children who were not able to discontinue the ICS use, the exercise-induced change in Rrs 5 Hz was greater than that in non-ICS users (β 0.70; 95%CI 0.080 to 1.3; P = 0.028), but this association did not remain in adjusted analysis ( Table 2 , Table S3 ). The results without the children using continuous ICS treatment before the follow-up visit were not markedly different (data not shown). To our knowledge, this is the first study to investigate the associations between the patient characteristics of the first acute severe virus-induced wheezing episode and the subsequent pulmonary function and bronchial reactivity later in childhood. As a main finding, atopic sensitization, both aeroallergen and food sensitization, during the first wheezing episode was associated with increased bronchial reactivity at preschool age. We did not find any significant association between the rhinovirus or its genome load, other virus infections, or other patient characteristics at study entry and the later pulmonary function or bronchial reactivity. Previous studies have reported that the early atopic sensitization Previous studies have shown parental asthma and maternal smoking to be associated with baseline pulmonary function and/or bronchial reactivity. 5, 8 Some studies have also found an association between these patient characteristics and decreasing pulmonary function during a follow-up until the age of 18 years. 6, 7 Vitamin D has been found to be potential in preventing infectious diseases and atopic illnesses through both innate and adaptive immune responses. [38] [39] [40] In our study, patient characteristic data were carefully assembled and 25-OH-D levels were analyzed. However, we did not find associations between any of these patient characteris- Earlier studies have shown decreased baseline pulmonary function in 20%-29% of cases 6-8 years after virus-induced bronchiolitis. 8, 9, 19 In our study, the proportion of pathological pulmonary function at baseline was low (3%). Our detection rate of exerciseinduced bronchial reactivity (11%) is also relatively low when compared to earlier studies (13%-62%). 8, 9, 19 In our study, twelve (32%) of the 37 children were not able to discontinue the ICS medication for asthma, which may partly explain the low detection rate of increased bronchial reactivity. However, in majority (68%) of the children using ICS, the medication was discontinued at least four weeks before the IOS testing. According to the Finnish guidelines, 41 Strengths of our study include the prospective design, new focus on the first wheezing episode, comprehensive viral diagnostics, the use of IOS for pulmonary function testing, good quality of the IOS measurements, and discontinuation of regular asthma controller medication in majority of asthmatic children before testing. Allergen-specific IgE was used for characterization of atopic sensitization. The children were carefully examined by a physician, and the standard questionnaire was used which provided detailed characterization of the children. 42 However, our study has some limitations. Most patients were hospitalized during the first acute wheezing episode, which makes these results only applicable for the most severe end of illness. The relatively small study population precluded analysis of rhinovirus species or the associations of other respiratory viruses with spirometry outcomes. Reasonable challenge in exercise test was ensured by continuous heart rate monitoring, but ventilation was not measured for this purpose. In conclusion, atopic sensitization diagnosed during the first acute severe wheezing episode was associated with increased bronchial reactivity and reduced lung function at preschool age. Clinically, these results suggest that testing for atopic sensitization at the time of first wheezing episode may have prognostic significance with respect to lung function. These results are also important to consider for the design of early intervention trials for secondary prevention of asthma. We thank Mrs Tiina Peromaa for her valuable help in conducting the exercise tests, Heidi Jokinen, biomedical laboratory scientist for her help in laboratory analyses, Dr Pekka Malmberg, PhD, for his guidance into the IOS methodology, and Mr Hans-Jüergen Smith (Jaeger, Würzburg, Germany) for providing us with the IOS device during this study. The authors have no conflict of interest in connection with this paper. 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